Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity

Abstract

Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a “proliferating” cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.

• Cancer initiating cells
• cancer stem cells
• connective tissue
• heterogeneity
• tumor microenvironment

Acknowledgments

We thank Alessandra Panvini Rosati for assistance and Dr Paola Corradino and Dr Martina Inoretti for bibliographic searches.

Declaration of interest

The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Our studies are funded by AIRC (Associazione Italiana per la Ricerca sul Cancro, IG10228 and IG15895), Italian Ministry of Health, PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, 2010NECHBX_003), and a Fondazione Umberto Veronesi fellowship (to KD). AB was a FIRC (Fondazione Italiana per la Ricerca sul Cancro) fellow and is a recipient of a fellowship from the University of Insubria.